It is now well established that cyclophilins represent one family of a large group of proteins which all possess peptidyl-prolyl cis/trans isomerase (PPIase) activity, the other families being FK-506-binding proteins and parvulins. Cyclophilins are ubiquitous enzymes, being found in all living organisms with high structural conservation across species. In humans there are seven major cyclophilins: cyclophilin-A, cyclophilin-B, cyclophilin-C, cyclophilin-D, cyclophilin-E, cyclophilin-40, and NK-cyclophilin. The most abundant protein is cyclophilin-A, which accounts for 0.6% of total cytosolic protein, whilst cyclophilin-D is found predominantly in cell mitochondria. Cyclophilin-B and cyclophilin-C are located largely in the endoplasmic reticulum whilst cyclophilin-E is located in the cell nucleus. Cyclophilin-40 is found in the cytosol, as is NK-cyclophilin (named as such because it was first discovered in human natural killer cells). The cyclophilins have also been observed to translocate between cellular compartments and, under certain circumstances, to be secreted, properties which contribute to their physiological functions. Cyclophilins have the specific enzymatic capability of accelerating the rate of cis/trans isomerisation of peptidyl-prolyl bonds and speed up the rate of folding of newly synthesised or denatured proteins. PPIases also play a role in the repair of proteins which have been damaged through exposure of cells to oxidation, ultraviolet radiation, thermal stress and pH changes. Cyclophilins A and B can be secreted from cells and the secreted proteins act as pro-inflammatory cytokines. Additionally, cyclophilins play a role in intracellular protein trafficking and cyclophilin-D has a modulatory role in the opening of the mitochondrial permeability transition pore.
The best known ligand and inhibitor for cyclophilins is cyclosporin A (CsA), binding to cyclophilins A, B, and D with nanomolar affinity. The well-known immunosuppressive activity of CsA is manifested not through cyclophilin inhibitory activity, but is a property of the complex formed with cyclophilin A: The whole complex binds to the protein calcineurin, a phosphatase whose activity is essential to initiate lymphokine gene transcription and the immune response. Thus, immunosuppression is the result of the formation of a ternary complex cyclosporin/cyclophilin A/calcineurin and displayed only by cyclosporin A and a few selected analogues or derivatives.